Abstract Joint damage and synovial inflammation in rheumatoid arthritis (RA) are influenced by genetic and environmental factors. In our previous studies, we have identified a panel of genes and pathways that could be targeted for RA by integrating DNA methylation data with transcriptomics and RA risk gene data. Built upon these results, we will construct a gene network composed of RA relevant genes whose expression profiles represent RA pathogenesis. We will develop a novel systems biology method to search for synergistic therapeutic targets in this gene network. Once completed, this proposed work will not only identify drug targets for effective treatment of RA but also shed light into understanding the regulatory mechanisms of disease formation.